647 Combination immunotherapy with pembrolizumab, lenvatinib, N-803 and dendritic cell vaccine targeting HER2 in patients with advanced or metastatic endometrial cancer

<h3>Background</h3> Despite the successful launch of cancer immunotherapy, the majority of the cancers do not respond to immunotherapy. The incidence and mortality of endometrial cancer (EC), the most common gynecologic cancer in the US, has been increasing. Five-year overall survival in patients with metastasis is around 20%. HER2 is expressed in up to 30% of non-endometrioid EC and anti-HER2 therapy is used as s standard treatment. An autologous dendritic cell vaccine that is transduced with an adenoviral vector expressing extracellular and transmembrane domains of HER2 (AdHER2DC) was well tolerated and showed a preliminary clinical benefit of 33.3% (NCT01730118). Importantly, no cardiotoxicity was noted and post-vaccination immunogenicity was confirmed.¹ The combination of pembrolizumab and lenvatinib in EC has shown an antitumor activity (response rate 33.8%) with manageable toxicity.² To overcome the resistance to immune checkpoint inhibitors, a combination of AdHER2DC to induce an anti-tumor immune response, lenvatinib to control the negative immune regulators and hostile tumor microenvironment and an immune stimulatory cytokine IL-15 superagonist N-803 and a PD1 inhibitor, pembrolizumab has been developed (figure 1). <h3>Methods</h3> This is an open-label, two-arm, phase I/II study of pembrolizumab, lenvatinib, N-803 (Anktiva), and AdHER2DC (figure 2). Objectives are 1) Phase 1: to estimate recommended Phase II dose (RP2D) of lenvatinib and 2) Phase 2: to assess the efficacy of a combination in participants with HER2-expressing EC as determined by the proportion of participants without progression at 6 months. Treatment will be delivered until progression or up to 1 year or unacceptable toxicity. Key eligibility includes individuals who are 18 years old or older with metastatic or locally advanced EC with HER2 immunohistochemistry (IHC) 1+, 2+ or 3+ and ECOG performance status 0–2. The participants must have received at least 1 line of systemic therapy and should have adequate organ function including cardiac ejection fraction by echocardiogram 50% or higher. Prior HER2 treatment is allowed but participants who received immune checkpoint inhibitors will be excluded. The participants will undergo apheresis to collect peripheral blood mononuclear cells which will be used to make AdHER2DCs. All participants in Arm 2 receiving lenvatinib RP2D will be included in assessing the Phase 2 primary endpoint. To allow for screen failure, enrollment will be set at 60 participants. <h3>Acknowledgements</h3> This research has been supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH). The National Cancer Institute, National Institutes of Health has Cooperative Research and Development Agreements (CRADAs) with ImmunityBio. <h3>Trial Registration</h3> NCT06253494. <h3>References</h3> Maeng H, Moore B, Bagheri H. Phase I clinical trial of an autologous dendritic cell vaccine against HER2 shows safety and preliminary clinical efficacy. <i>Front Oncol</i> 2021;<b>11</b>(4979). Makker V, Colombo N, Herráez A. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: updated efficacy and safety from the randomized phase III Study 309/KEYNOTE-775. <i>J Clin Oncol</i> 2023;<b>41</b>(16):2904–10. <h3>Ethics Approval</h3> The study was approved by the NIH IRB Ethics, approval number IRB001557.